Sidney Udenfriend
National Institutes of Health Bethesda, Maryland
I
I
The Role of the Biothemist in the Search for New Therapeutic Agents
Natural products and their extracts were already in use as therapeutic agent,s when recorded history began. Many of these ancient remedies are in use even today, in modified form. However, the application of some degree of rational approach to the development of therapeutic agents befan with the introduction of organic chemistry and modern biology, bacteriology, parasitology, physiology, etc. Organic chemists isolated active compounds from natural products, determined their structures and, as they improved their techniques, they synthesized related compounds with even greater activity. Biologists became more sophisticated, too, and as clinicians became more experimental, scores of valuable therapeutic agents were introduced: anaesthetics, analgesics, vaccines, antibacterial agents, antipyretics. All these were introduced successfully long before the advent of modern biochemistry. At the present time the team of organic chemist, biologist, and clinician still produces new agents at a rate which, if anything, is increasing. Reserpine, thoraziue, imipramine, and diurel are but a few examples of the continuing success of this approach. However, even with these notable successes most of us still feel that there will eventually be a more rational way to approach the problem of developing new therapeutic agents. One of the first suggestions that therapy might benefit from a biochemical approach followed the introduction of sulfonamides and the demonstration of the growth requirements for the related compound, p-aminobenzoic acid. As it became apparent that the structural relationship between these two could have Presented as part of the 50th Anniversary Symposium, Division of Medicinal Chemistry, American Chemical Society, September 16, 1959, Atlsntic City, New Jersey.
---
- -
-
-
something to do with the antibacterial activity, the notion of antimetabolites, as therapeutic agents, mas introduced. This concept has already helped in our understanding of drug action. However, the major limitation to a more successful application of antimetabolites to therapy has been our meager understanding of the biochemical and physiological mechanisms of the metabolites themselves. As biochemistry continues to make progress in explaining the mechanisms of living processes, it becomes apparent that it provides a wealth of information which it should be possible to put to use in the development of therapeutic agents. Each new enzyme and each new metabolic route is potentially capable of leading to some advance in therapy. At the recent meetings of the Pharmacology Society in Miami, it became apparent that large strides are being made in providing biochemical answers to a variety of therapeutic problems. Strominger reported on the effects of penicillin and other antibiotics on the synthesis of bacterial cell wall. This work combines the most fundamental with the most practical in bacteriological research. Sutherland and Rall reported on the relationship of the effects of epinephrine and glucagon t o a new metabolite, cyclic adenylic acid. These and many other exciting facts were reported a t the teaching seminar, all of them presenting some biochemical findings relating to physiological action or therapy. The tenor of these meetings indicates that biochemistry, without question, has found a place in the quest for therapeutic agents. The problem is, where does the biochemist fit in in the team of organic chemist, biologist, and clinician which i s already functioning aith reasonable successB Biochemistry is an immense science concerning itself
Volume 37, Number 4, April 1960
/
189
with all matters relating chemistry to l i e processes. It is apparent that advances in the remotest areas have far-reaching implications, many of which may contribute directly or indirectly to therapy. However, I would like to limit my discussion to the direct applications of biochemistry to therapy. These include: (1) Attempts to explain the actions of older drugs; (2) Help in setting up of proper regimens for existing drugs; explanations of toxicity, etc.; (3) Attempts to develop new therapeutic agents.
I will be the first to admit that. biochemistry has yet t o offer a completely rational explanation for the actions of any existing drng. However, our knowledge is still only fragmentary and every day new biochemical processes and principles are uncovered which contribute important leads. In this area we have suffered m m y disappointments. However, these have taught us valuable lessons too. Thus, the demonstration that anaesthetics and analgesics. in uitro, can uncouple oxidative phospborylation appeared significant to an earlier, more naive, biochemistry. Now we realize that such a theory contributed little to our fundamental understanding and to the practical development of improved anaesthetics. While our findings in this area were negative they taught us to look for more selective mechanisms and specific sites t b explain the actions of such specific agents. We also know now that biochemical effects demonstrated, in uitro, must be duplicated in viva a t dosages which are in the therapeutic range, in order t o be meaningful. Obviously reliable information concerning the mode of action of a wellknown drug can lead to the development of newer ones. If it inhibits a certain enzyme, other inhibitors can be tried. If it releases certain hormonal agents, related compounds may be more active or less toxic. These can all be followed by screening with relatively simple biochemical methods. The second important aspect of biochemistry concerns the application of analytical procedures to make sure that agents with certain therapeutic potential are used properly. Are they absorbed through the gut? Do they penetrate into the pertinent tissues when administered in a given dose via a given route? More important, does a drug developed to produce a given biochemical effect actually produce that effect in patients, in the dosages employed for therapy. Information of this type must be channeled back before further progress can be made in our understanding of drug action or in the development of new agents. I would like to give as an example the current use of monoamine oxidase (MAO) inhibitors. These agents were first used experimentally for the treatment of mental disorders because they were known to influence anline metabolism in the central nervous system of animals. Although this is of great interest it itself does not provide fundamental knowledge since we do not as yet know how the amines themselves act. However, screening for such activity in vitro and in viva has brought forth many more compounds with similar activity. Now even though these compounds were introduced over two years ago it is only recently that methods are being developed to determine whether these agents do indeed inhibit MA0 in patients and to what extent. I have heard many individuals, some in 190
/
Journal of Chemical Education
important positions in academic research and pharmaceutical industry, state that they doubted that the therapeutic actions of these drugs were due to this specific biochemical effect. Now there is something wrong with such reasoning. If there is no connection, why the very elaborate and expensive screening and synthetic programs? If, on the other hand, there is a direct relationship, why not invest sufficient time and money to establish this beycmd doubt? The third area where biochemistry can contribute is the most speculative but the most exciting; that is in the development of entirely new types of therapeutic agents. Before I go into this I would like to point out that none of the sciences today is capable of predicting the therapeutic effects which may result from a particular manipulation of a biological system. As biochemists all we can hope to do is to modify specific biochemical reactions in the hope that we will obtain a physiologic response in viva dependent on the activation or inactivation of that specific site. However, the exact nature of the over-all i n uiuo response of such a new specific reagent is unpredictable and its therapeutic applications even more so. Nevertheless, biochemists can point t o many areas and say that chemical manipulation here or there can lead to interesting compounds. If one in ten of these turns out to be a useful drng I would consider this an excellent achievement. Where does the biochemist turn for his leads? To chemical steps in the formation of substances specific for given tissues, organs, or chemical processes. Examples of these would by 7-aminobutyric acid (GABA) in brain; hydroxyproline in connective tissue; chemical steps in parasite metabolism: specific transport mechanisms of various metabolites into different cells; storage and release mechanisms of hormones and related humoral agents; chemical steps in inactivation of physiologically active agents; isolation and determination of substances from nervous tissue, eye pigments, etc. All these should be amenable to the influences of specific chemical agents and could lead to interesting pharmacological effects. Some of these chemical agents could even turn out t o be therapeutically actite. Now it must be apparent to most of you that I have dealt with biochemical contributions and advances in rather general terms. I could go into specific examples from our own work and that of others. However, I would like to take this opportunity to discuss the role of the biochemist within pharmaceutical industry. Biochemists in academic laboratories have benefited greatly from pharmaceutical industry both directly and indirectly, through fellowships, grants, gifts of chemicals, consultantships, collaborations, etc. I n that respect chemical and pharmaceutical industry have been invaluable to the biochemist. However, what of the practice of biochemistry within industry? What about the biochemist who finds himself within industry? In connection with this matter, see table which follows. As you can see, in the first quarter of 1957 and 1958 industrial organic chemists and pharmacologists accounted for 1in 5 papers in their respective professional journals. The Journal of the American Chemical Society has similar values. However, only l in 300 was published in the Journal of Biological Chemistry, and that one was in collaboration with a university group.
Publications b y Scientists in Chemical and Pharmaceutical Industry
January, February, March Journal
1857
19.58
Total
% of Total
J. Organic Chemistry 48/261 37/206 85/467 18 J. Phamacol. and Ezp. Therap. 9/38 4/36 13/74 18 3. Biolo@cal Chemistry Archives of Biochemistry and Bionhusies
0/146
1/158
1/304
4/90
7/87
11/177
0.3 6
In the Archives of Biochemistry and Biophysics industry published 1 in 17. Half of these concerned analytical methods. What is the significance of this7 To me it indicates that a t a time when the biochemist is making great strides in mechanisms of living processes chemical and pharmaceutical industry are not making direct use of his talents as a biochemist. The limited publications in the biochemical journals indicate a number of things: Relatively few biochemists are employed by industry. Many who are called such are in effect organic chemists. Those biochemists who are in industry cannot or do not pursue lines of research resulting in papers acceptable by their professional journals. By contrast organic chemists and pharmacologists can do so readily. The impression I have of much of research in pharmaceutical industry is that it still adheres to the principle of leadelship by organic chemists and pharmacologists and that these two utilize the biochemist in a service capacity. Thus, the biochemist may be told: "We have a new compound; develop a method for assay. How is this given compound metabolized? What enzyme does our new drug affect?" Obviously these are necessary services which a biochemistry laboratory in industry should supply. They are bread and butter functions, but the biochemist cannot survive as a scientist on bread and butter alone. If he is to flourish as a distinct member of the research team, he shonld be permitted to explore biochemical leads on his own, and to make sn~gestionsto the organic chemists and pharmacologists in turn. There is no reason why a biochemistry laboratory in industry should not be able to conduct research which is a t one and the same time intellectuauy stimulating and also of potential value in developing new therapeutic agents. With all the interest in drugs which can influence monoamine oxidase, catechol methylpherase, and amino acid decarboxylases, why shouldn't biochemists in industry work on purifying these enzymes? It is certainly possible that. identification of the cofactor of
MA0 could lead to a better understanding of how MA0 inhibitors work and therefore to new agents. In any event isn't it desirable to have members on the staff who know more about the problem than the mere bioassay procedure involved in screening? The biochemistry of the bacterial cell wall would also be an excellent and timely study leading to many fundamental and practical things. Too frequently the industrial biochen~istis permitted only to pursue the screening portion of a research problem and leave the most exciting portions for others. This can be quite frustrating. Alternatively his talents may be used for more biological or chemical programs. I don't believe that i t is a luxury to permit biochemists to carry on stimulating biochemical research programs. One can point to many departments outside industry from which numerous practical contributions continue t o come year after year. Would not such departments be just as useful within an industrial framework? I believe they would. However, careful examination reveals that a biochemistry laboratory to be able to function so that it can satisfy both the research requirements and day to day developmental studies would have to he much larger than any in industry today. I believe that there is a critical size of a laboratory below which a company cannot make proper use of a biochemical group even if it so desires. Increasing the professional and technical manpower of a biochemical laboratory beyond a certain point increases the thinking and research potential far in excess of the mere number of individuals hired. I believe that in its initial overtures to biochemistry industry is doing what appears to be sensible; that is, building up the size of lahoratones slowly as one would do in any experimental venture. However, I think that this is a serious error. I firmly believe that the first company which decides to build a department of biochemistry in the same manner as is done in a university or research institute will find itself in a very favorable position. What I mean by this is not only the setting up of a department under the direction of an outstanding investigator but the understanding that he will be permitted to select a staff of his own choosing and to participate in those areas of research which are of interest to him and his colleagues. The contributions from such a department to the company should then be measured not in the number of products but in the number of interesting findings of biological or pharmacological significance. With a sufficient number of these findings the organic chemist, biologist, and clinician should be able to increase significantly their rate of development of new therapeutic agents.
Chem Gems
Dializer
Quartz
S t e r e o Chemistry
Reprinted by permission from the "Scimtwisls" page of the Gaesee Valley CHEMzlnieations (Rochester Section, ACS). Volume 37, Number 4, April 1960
/
191
